De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function

Abstract

The dysfunction and clonal constriction of tumor-infiltrating CD8⁺ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8⁺ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD⁺) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8⁺ T cell metabolic and functional fitness. De novo NAD⁺ synthesis is involved in CD8⁺ T cell metabolism and antitumor function. KP-derived NAD⁺ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD⁺ synthesis limits CD8⁺ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD⁺ regulates the CD8⁺ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD⁺ synthesis could restore CD8⁺ T cell metabolic fitness and antitumor function.

Keywords: CP: Cancer; CP: Metabolism.